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Cited by 3RNA Interference and Gene DeliveryRNA and protein synthesis mechanismsRNA modifications and cancer

A comprehensive analysis of the use of nucleoside analogues in RNA therapeutics

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Kukushkina-Zvezdova, Alisa A., Zherebtsova, Anna A., Telegina, Darya V., Skvortsov, Ivan A., Ivanov, Roman A., Reshetnikov, Vasiliy V.·2026·Journal of Translational Medicine
DOI 10.1186/s12967-026-08083-4PMC PMC13188432
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Abstract

BACKGROUND: mRNA therapeutics represent a promising frontier in the development of vaccines, anti-cancer treatments, and gene replacement therapies. The mRNA platform facilitates the rapid design of effective and safe candidates. However, native mRNA molecules are inherently characterized by limited stability and high reactogenicity, which may compromise their in vivo efficacy. The incorporation of modified nucleoside analogues can address these challenges by extending the mRNA half-life and subsequently enhancing protein expression. MAIN BODY: Despite the discovery and widespread adoption of pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ) in mRNA therapeutics, these modifications have not fully addressed all inherent limitations of mRNA-based platforms. Consequently, identifying novel nucleoside analogues, their combinations, and alternative therapeutic strategies remains a critical area of research. This review provides a comprehensive overview of how commonly used nucleoside analogues influence mRNA stability, translation, and immunogenicity, while also discussing their natural distribution patterns in native mRNA. Furthermore, we examine experimental in vitro and in vivo data regarding the application of non-canonical nucleosides in cell and animal models and evaluate the future prospects of modified mRNA-based therapies. CONCLUSION: In conclusion, this review provides an extensive analysis of the properties of modified nucleosides employed in mRNA formulations and characterizes their impact on the overall efficacy of mRNA-based therapeutics in detail.

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  • Inclusion of specific untranslated regions is a promising strategy to enhance stability and efficacy of mRNA therapeutics.

    “Recent studies demonstrate that, in addition to the incorporation of modified nucleosides, the inclusion of specific untranslated regions represents a highly promising strategy to enhance the stability and efficacy of mRNA therapeutics [12][13][14][15][16].”

    From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [16]

    In “Synthesis of mRNA with region-specific modifications” (page unavailable), the review says that optimizing mRNA secondary structure for stability and translatability takes UTR structures into account. It does not specifically say that including particular untranslated regions enhances therapeutic stability and efficacy; its proposed strategy concerns sequence or structural optimization and region-specific nucleoside modifications. (LLM, conf=0.81)

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Cited by

Sorted by citations

Authors
Kukushkina-Zvezdova, A. A., Zherebtsova, A. A., Telegina, D. V., Skvortsov, I. A., Ivanov, R. A., & Reshetnikov, V. V.
Affiliations
Sirius University of Science and Technology (RU)
Corresponding author
Reshetnikov, Vasiliy V.
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2026-04-07
Volume
24
Issue
1
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-026-08083-4
PMC
PMC13188432
OpenAlex
W7150822187
Cited by
3
References
25
Citations by year
2026: 3
FWCI
1.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
«Sirius» Federal Territory (Agreement № 3-03 date February 18, 2025)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
mRNA therapeutics, nucleoside analogues, modified nucleosides, mRNA stability, pseudouridine, N1-methylpseudouridine, mRNA translation, immunogenicity, mRNA vaccines, gene replacement therapy, cancer therapy
MeSH terms
Animals, Humans, Nucleosides, RNA, RNA, Messenger, RNA Stability

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